Department of Neurological Surgery, University of California at San Francisco, San Francisco, CA, United States of America (USA); School of Medicine, Wayne State University, Detroit, MI, United States of America (USA).
Department of Neurological Surgery, University of California at San Francisco, San Francisco, CA, United States of America (USA).
Semin Cancer Biol. 2020 Nov;66:75-88. doi: 10.1016/j.semcancer.2019.08.031. Epub 2019 Aug 28.
Autophagy is a lysosomal-dependent degradation process that is highly conserved and maintains cellular homeostasis by sequestering cytosolic material for degradation either non-specifically by non-selective autophagy, or targeting specific proteins aggregates by selective autophagy. Autophagy serves as a protective mechanism defending the cell from stressors and also plays an important role in enabling tumor cells to overcome harsh conditions arising in their microenvironment during growth as well as oxidative and non-oxidative injuries secondary to therapeutic stressors. Recently, autophagy has been implicated to cause tumor resistance to anti-angiogenic therapy, joining an existing literature implicating autophagy in cancer resistance to conventional DNA damaging chemotherapy and ionizing radiation. In this review, we discuss the role of angiogenesis in malignancy, mechanisms of resistance to anti-angiogenic therapy in general, the role of autophagy in driving malignancy, and the current literature in autophagy-mediated anti-angiogenic therapy resistance. Finally, we provide future insight into the current challenges of using autophagy inhibitors in the clinic and provides tips for future studies to focus on to effectively target autophagy in overcoming resistance to anti-angiogenic therapy.
自噬是一种溶酶体依赖性降解过程，高度保守，通过隔离细胞质物质进行降解来维持细胞内稳态，这种降解方式要么是非特异性的非选择性自噬，要么是通过选择性自噬靶向特定的蛋白质聚集体。自噬作为一种保护机制，可使细胞免受应激源的侵害，在肿瘤细胞生长过程中，它还在使肿瘤细胞适应微环境中的恶劣条件方面发挥着重要作用，同时还能耐受治疗应激源引起的氧化和非氧化损伤。最近，自噬被认为会导致肿瘤对抗血管生成治疗产生耐药性，这加入了现有的文献，表明自噬会导致肿瘤对常规的 DNA 损伤化疗和电离辐射产生耐药性。在这篇综述中，我们讨论了血管生成在恶性肿瘤中的作用、一般抗血管生成治疗耐药的机制、自噬在驱动恶性肿瘤中的作用，以及目前关于自噬介导的抗血管生成治疗耐药性的文献。最后，我们对目前在临床上使用自噬抑制剂所面临的挑战提供了未来的见解，并为未来的研究提供了一些建议，以集中精力通过靶向自噬来克服抗血管生成治疗的耐药性。
